Journal article
TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes
PLoS genetics, Vol.18(5), pp.e1010207-e1010207
05/17/2022
DOI: 10.1371/journal.pgen.1010207
PMCID: PMC9159589
PMID: 35580127
Abstract
In developing melanocytes and in melanoma cells, multiple paralogs of the Activating-enhancer-binding Protein 2 family of transcription factors (TFAP2) contribute to expression of genes encoding pigmentation regulators, but their interaction with Microphthalmia transcription factor (MITF), a master regulator of these cells, is unclear. Supporting the model that Tfap2 facilitates MITF's ability to activate expression of pigmentation genes, single-cell seq analysis of zebrafish embryos revealed that pigmentation genes are only expressed in the subset of mitfa-expressing cells that also express Tfap2 paralogs. To test this model in SK-MEL-28 melanoma cells we deleted the two TFAP2 paralogs with highest expression, TFAP2A and TFAP2C, creating TFAP2 knockout (TFAP2-KO) cells. We then assessed gene expression, chromatin accessibility, binding of TFAP2A and of MITF, and the chromatin marks H3K27Ac and H3K27Me3 which are characteristic of active enhancers and silenced chromatin, respectively. Integrated analyses of these datasets indicate TFAP2 paralogs directly activate enhancers near genes enriched for roles in pigmentation and proliferation, and directly repress enhancers near genes enriched for roles in cell adhesion. Consistently, compared to WT cells, TFAP2-KO cells proliferate less and adhere to one another more. TFAP2 paralogs and MITF co-operatively activate a subset of enhancers, with the latter necessary for MITF binding and chromatin accessibility. By contrast, TFAP2 paralogs and MITF do not appear to co-operatively inhibit enhancers. These studies reveal a mechanism by which TFAP2 profoundly influences the set of genes activated by MITF, and thereby the phenotype of pigment cells and melanoma cells.
Details
- Title: Subtitle
- TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes
- Creators
- Colin Kenny - Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa, United States of AmericaRamile Dilshat - University of IcelandHannah E Seberg - Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa, United States of AmericaEric Van Otterloo - University of IowaGregory Bonde - University of IowaAnnika Helverson - Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa, United States of AmericaChristopher M Franke - University of IowaEiríkur Steingrímsson - University of IcelandRobert A Cornell - University of Iowa
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.18(5), pp.e1010207-e1010207
- DOI
- 10.1371/journal.pgen.1010207
- PMID
- 35580127
- PMCID
- PMC9159589
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7404
- eISSN
- 1553-7404
- Publisher
- Public Library Science
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01-AR062457; DOI: 10.13039/100016025, name: American Association for Anatomy, award: Postdoctoral fellowship; name: Research Fund of Iceland, award: 207067; name: Research Fund of Iceland, award: 217768
- Language
- English
- Date published
- 05/17/2022
- Academic Unit
- Anatomy and Cell Biology; Surgery; Craniofacial Anomalies Research Center; Dental Research; Periodontics
- Record Identifier
- 9984284353102771
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